1. Field of the Invention
The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to the synthesis of diketopiperazines and related compounds.
2. Description of the Related Art
It has been reported that tryprostatins A and B (which are diketopiperazines consisting of proline and isoprenylated tryptophan residues), and five other structurally-related diketopiperazines, inhibited cell cycle progression in the M phase, see Cui, C. et al., 1996 J Antibiotics 49:527-33; Cui, C. et al. 1996 J Antibiotics 49:534-40, and that these compounds also affect the microtubule assembly, see Usui, T. et al. 1998 Biochem J 333:543-48; Kondon, M. et al. 1998 J Antibiotics 51:801-04. It is known that when an abnormality arises in the control mechanism of the cell cycle, cancer or an immune disorder may occur. Accordingly, substances that regulate the cell cycle may be effective antitumor agents and immune suppressors. Thus, new methods for producing eukaryotic cell cycle inhibitors are needed as antitumor and immune-enhancing compounds, and should be useful in the treatment of human cancer as chemotherapeutic, anti-tumor agents. See, e.g., Roberge, M. et al., Cancer Res. (1994), 54, 6115-21.
Diketopiperazine-type metabolites have been isolated from various fungi as mycotoxins, see Horak R. M. et al., 1981 JCS Chem Comm 1265-67; Ali M. et al., 1898 Toxicology Letters 48:235-41, or as secondary metabolites, see Smedsgaard J. et al., 1996 J Microbiol Meth 25:5-17. The chemical synthesis of one type of diketopiperazine-type metabolite, phenylahistin, has been described by Hayashi et al. in J. Org. Chem. (2000) 65, page 8402.
Monodehydro-diketopiperazines have also been isolated from various organisms (e.g., from Penicillium piscarium, Kozlovsky et al., Product Lett. (2000) 14, 333; from Anthosigmella aff. Raromicrosclera, Tsukamoto et al. Tetrahedron (1995) 51, 6687; from Streptomycesnoursei, Shin et al. Heterocycles (1980) 14, 1767; Viridamine from Penicillium viridicatum, Holzafpel et al. South Afr. J. Chem. (1977) 30, 197; (−)-Phenylahistin from Aspergillus ustus, Kanoh et al. Bioorg Med. Chem. (1999) 7, 1451; and Aurantiamine from Penicillium aurantiogriseum, Larsen et al. Phytochemistry (1992) 31, 1613).
With the incidences of cancer on the rise, there exists a particular need for chemically producing a class of substantially purified diketopiperazine-type metabolite-derivatives having animal cell-specific proliferation-inhibiting activity and high antitumor activity and selectivity. There is therefore a particular need for an efficient method of synthetically producing substantially purified diketopiperazine-type metabolite-derivatives.
Prior syntheses of monodehydro-2,5-diketopiperazines have been problematic due to racemization at the side chain site opposite the dehydro side chain site. Thus, there is a need for synthetic methods for producing stereochemically pure diketopiperazines.